Malaria remains one ofthe most important infectious diseases woridwide, with children under five years of age and pregnant women living in Africa being most severely affected. The primary tools currently available for malaria prevention include the use of insecticide treated bednets (ITNs) and intermittent preventive treatment (IPT) of pregnant women with sulfadoxine-pyrimethamine (SP). However, there are limitations with these interventions and the burden of malaria remains high in many parts of Africa despite recent increases in coverage levels. New potential tools for the prevention of malaria in high risk populations include the use of more effective drugs for IPT in pregnancy and expanding IPT for use in infants. Dihydroartemisinin- piperaquine (DP) is a new antimalarial drug that has been shown to be highly effective and safe for the treatment of malaria in pregnant women and infants. The extended post-treatment prophylactic effect of DP makes it attractive for use as a chemopreventive drug. It is hypothesized that highly effective IPT with DP during pregnancy and infancy will greatly reduce the burden of malaria and improve the development of naturally acquired antimalarial immunity. This will be a double-blinded controlled phase III trial of 300 HIV uninfected pregnant women and the children born to them. The study interventions will be divided into two phases. In the first phase, HIV uninfected women in their 1st or 2nd pregnancy at 12-20 weeks gestation will be randomized to IPTp with 2 dose SP or 2 dose DP or monthly DP. In the second phase ofthe study all children born to mothers enrolled in the study will be followed from birth until they reach 36 months of age. Children will be randomized to receive monthly q 3 monthly DP or monthly DP between 2-24 months of age and then followed for 1 additional year after the intervention is stopped. The specific aims will be as follows: 1) To compare the risk of placental malaria among HIV uninfected pregnant women randomized to receive IPTp with 2 dose SP vs. 2 dose DP vs. monthly DP. 2) To compare the incidence of malaria among infants randomized to receive q 3 monthly DP vs. monthly DP between 2-24 months of age. 3) To compare the incidence of malaria among infants and children following the two phases of the intervention. RELEVANCE (See instructions): In areas of high malaria transmission intensity the burden of malaria remains high among pregnant women and infants despite the use of currently available control interventions. Aggressive and strategic use of highly effective drugs for the prevention of malaria during pregnancy and infancy may dramatically reduce malaria associated morbidity and improve the development of antimalarial immunity.